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Aβ reduction at early disease stages prevents progression of cerebral amyloid angiopathy in a mouse model of hereditary cerebral hemorrhage with amyloidosis - Dutch type

Schelle, Juliane and Wegenast-Braun, Bettina and Fritschi, Sarah and Kaeser, Stephan A and Häsler, Lisa M and Wolfer, David and Mueggler, Thomas and Shimshek, Derya and Neumann, Ulf and Dodt, Hans-Ulrich and Staufenbiel, Matthias and Jucker, Mathias (2019) Aβ reduction at early disease stages prevents progression of cerebral amyloid angiopathy in a mouse model of hereditary cerebral hemorrhage with amyloidosis - Dutch type. Annals of Neurology. ISSN 0364-51341531-8249

Abstract

Introduction: Deposition of -amyloid peptide (A) within cerebral vessels (cerebral amyloid angiopathy, CAA) contributes to intracerebral bleedings and altered brain function. CAA occurs with aging and to various degree in Alzheimer’s disease.
Methods: APPDutch mice model hereditary cerebral hemorrhage with amyloidosis – Dutch-type (HCHWA-D) and develop CAA in the vast absence of parenchymal amyloid. 3D-ultramicroscopy and immunoassays were used to assess CAA onset and progression. An inhibitor to the β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) was used to lower A generation.
Results: CAA was first detected in frontal leptomeningeal and superficial cortical vessels followed by vessels penetrating the cortical layers. Upon CAA onset, A in the CSF was decreased. BACE1-inhibition initiated at the onset of CAA, and continued for 4 months, largely prevented CAA progression and associated microgliosis.
Discussion: Results provide a preclinical basis for A-reducing treatments in patients at risk of CAA and in presymptomatic HCHWA-D mutation carriers.

Item Type: Article
Date Deposited: 27 Aug 2019 00:45
Last Modified: 27 Aug 2019 00:45
URI: https://oak.novartis.com/id/eprint/39054

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